title: Identification of a serine protease inhibitor which causes inclusion vacuole reduction and is lethal to Chlamydia trachomatis.
abstract: The mechanistic details of the pathogenesis of Chlamydia, an obligate intracellular pathogen of global importance, have eluded scientists due to the scarcity of traditional molecular genetic tools to investigate this organism. Here we report a chemical biology strategy that has uncovered the first essential protease for this organism. Identification and application of a unique CtHtrA inhibitor (JO146) to cultures of Chlamydia resulted in a complete loss of viable elementary body formation. JO146 treatment during the replicative phase of development resulted in a loss of Chlamydia cell morphology, diminishing inclusion size, and ultimate loss of inclusions from the host cells. This completely prevented the formation of viable Chlamydia elementary bodies. In addition to its effect on the human Chlamydia trachomatis strain, JO146 inhibited the viability of the mouse strain, Chlamydia muridarum, both in vitro and in vivo. Thus, we report a chemical biology approach to establish an essential role for Chlamydia CtHtrA. The function of CtHtrA for Chlamydia appears to be essential for maintenance of cell morphology during replicative the phase and these findings provide proof of concept that proteases can be targeted for antimicrobial therapy for intracellular pathogens.
authors.affiliation: Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Kelvin Grove, Qld, 4059, Australia.
authors.forename: Sarina
authors.initials: S
authors.lastname: Gloeckl
authors.forename: Vanissa A
authors.initials: VA
authors.lastname: Ong
authors.forename: Pooja
authors.initials: P
authors.lastname: Patel
authors.forename: Joel D A
authors.initials: JD
authors.lastname: Tyndall
authors.forename: Peter
authors.initials: P
authors.lastname: Timms
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Beagley
authors.forename: John A
authors.initials: JA
authors.lastname: Allan
authors.forename: Charles W
authors.initials: CW
authors.lastname: Armitage
authors.forename: Lynne
authors.initials: L
authors.lastname: Turnbull
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Whitchurch
authors.forename: Melisa
authors.initials: M
authors.lastname: Merdanovic
authors.forename: Michael
authors.initials: M
authors.lastname: Ehrmann
authors.forename: James C
authors.initials: JC
authors.lastname: Powers
authors.forename: Jozef
authors.initials: J
authors.lastname: Oleksyszyn
authors.forename: Martijn
authors.initials: M
authors.lastname: Verdoes
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
authors.forename: Wilhelmina M
authors.initials: WM
authors.lastname: Huston
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002460:Cell Line; D002692:Chlamydia trachomatis / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D004151:Dipeptides / Q000378:metabolism*; D020043:Genes, Essential; D022781:Hepatocytes / Q000382:microbiology; D006801:Humans; D002479:Inclusion Bodies / Q000382:microbiology*; D050296:Microbial Viability / Q000187:drug effects*; D008853:Microscopy; D063065:Organophosphonates / Q000378:metabolism*; D057057:Serine Proteases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004151:Dipeptides; C000611216:JO146 compound; D063065:Organophosphonates; D015842:Serine Proteinase Inhibitors; D057057:Serine Proteases